Diabetes refers to a disease that plasma glucose level is maintained above normal range (>126 mg/dl at fasting status), or hyperglycemia, due to the malfunction of body homeostasis by various reasons. In United States alone, 6.2% of the population (17 million) is suffering from the diabetes which has many complications associated with the macro and micro vascular disease such as coronary heart disease, stroke, hypertension, neuropathy, nephropathy, retinopathy. By American Diabetes Association, adults with diabetes have 2-4 time higher death rate of heart disease and chance of stroke. Each year, 12,000-24,000 people lose their sight and 30,000 people lose their low limb due to diabetes. Control of the blood glucose level significantly decreases the morbidity and complications related with diabetes.
There are two types of diabetes. Type I is a disease which body does not produce insulin due to the destruction of β-cell and type II is a disease which body does not fully utilize insulin due to the increased insulin resistance of the body. Over 90% of the diabetes patients are type II.
Administration of the sulfonylurea drugs such as glyburide and glimepiride stimulate pancreatic β-cell to produce more insulin which compensate the insulin resistance.
Long term use of these insulin secretagogues results in the eventual exhaustion of the β-cell and induction of more resistance at the end. Acute hypoglycemia due to temporal excess of insulin is another adverse effect of these drugs.
Biguanides such as Metformin and Phenformin increase insulin sensitivity to a certain extent but lactic acidosis, nausea and diarrhea are reported as adverse effects.
TZD (thiazolidinedione) type drugs are a more recent addition to the market. They are known to enhance insulin sensitivity by stimulation of PPARγ, peroxisome proliferators activated receptor γ, which is critical for adipocyte differentiation and the modulation of genes involved in energy storage and utilization. TZD drugs are reported to markedly enhance insulin sensitivity and obviate the occurrence of hypoglycaemia but some of it have serious liver toxicity issues and Rezulin was withdrawn from the US market in 2000. Currently, researchers are actively seeking non-TZD based drugs to avoid the liver toxicity potentially associated with thiazolidinedione functional group.
PPARα is reported to be involved in β-oxidation of the fatty acids. Ligands of PPARα such as clofibrate and fenofibrate are known to reduce triglyceride and LDL significantly. As many diabetic patients are accompanied with obesity, dyslipidemia, atherosclerosis and high level of LDLs which worsen the complications, efforts have been made to discover PPARα and PPARγ dual agonist which may correct the abnormalities of blood glucose and dyslipidemia at the same time. Examples are JTT-501 (H. Shinkai et al, Drugs Future, 1999, 24), 2-Methyl-2{4-[2-(5-methyl-2-aryloxazol-4-yl)ethoxy]phenoxy}propionic acid (Dawn A. Brooks et al, J. Med. Chem., 2001, 44, 2061-4) and 3-[4-(2-carbazol-9-yl-ethoxy)-phenyl]-2-ethoxy-propionic acid (P. Sauerberg et al, J. Med. Chem., 2001, 44, 2061-4).
The present invention is concerned with the general structure of Formula I, which is a new class of compounds which do not belong to the typical structure of PPARα and PPARγ class, yet effective for lowering blood glucose, insulin and fatty acids. Compounds of general structure of Formula I have potentials as a new class of drugs that has beneficial effects over the current drugs and candidate materials.